Type 1 diabetes (T1D) is the most common chronic disease in children and is very costly to both the individual and society. The long-term objective is to uncover the mechanisms of spontaneous T1D development in the BB rat that serves as a model of the human disease. In this program project we use molecular genetics tools to dissect the loci associated with BB rat diabetes; the major histocompatibility complex (MHC) on chromosome 20 (Iddm1), the lymphopenia-inducing Ian5 mutation on chromosome 4 (Iddm2llyp) and two diabetes resistance loci inherited from F344 rats; Iddm3 on chromosome 2, and a fourth factor (Iddm19) on chromosome 15. We have made substantial progress in identifying the Ian5 mutation for lyp and its transgenic rescue as well as the mapping of the two resistance loci. Our primary goal in Project 1 is to study how the Ian gene family confers risk for lymphopenia and T1D. For the renewal, we build on our recent success and have added new strategies that take advantage of the progress made in the rat, mouse and human genome projects. Specifically, we propose in three specific aims to test the hypotheses that 1) the coordinate expression of the newly discovered family of anti-apoptopic Immune Associated Nucleotide (Ian) proteins controls lymphopenia and age-dependent onset of T1D, or alternatively that 2) a genetic factor(s) up-stream of the Ian family of genes is linked specifically to T1D development and, finally that 3) Iddm3 and Iddm19 are susceptibility factors in the BBDR rat interacting with MHC and the Ian family of genes to induce T1D. In collaboration with projects 2 and 3, research designs and methods for testing these hypotheses will include the complete characterization of the entire family of Ian genes (7/11 members characterized so far), their coordinate expression and expression in effector and target islet beta cells. We will use our newly developed congenic BBF line, which is a lymphopenic DR.(lypllyp) rat that does not develop T1D due to the introgression of a 23 Mb diabetes-resistant F344 genomic fragment up-stream of the Ian5 mutation. Together with project 2, we will study the function of critical Ian genes in transgenic rats and mice and with Project 3, we will develop congenic Iddm3 and chromosome 15 (Iddm19) DR.(lypllyp) rats to study the expression of more than 200 candidate genes conferring diabetes resistance as F344 alleles. The identification of genetic factors on these four different chromosomes should make it possible to identify the final common pathway(s) that control spontaneous T1D development in the BB rat. As some of these loci are also important to human T1D, elucidation of molecular mechanisms that govern spontaneous BB rat T1D may allow the identification of novel targets for therapeutic interventions to prevent or cure T1D.